Hypericin is a constituent of plants belonging to the genus Hypericum. It was isolated from this natural source in a chemically pure state by H. Brockmann et al. (Ann. 1942, 553, 1). Hypericin always appears in nature accompanied by the chemically related compound pseudo-hypericin.
Hypericin has gained interest in the last few years by virtue of the discovery of its anti-viral and anti-retroviral activity (cf., inter alia, European Patent Application No. 0 256 452 and G. Lavie et al., Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 596). Hypericin is now considered as a potentially effective drug against a number of diseases caused by the above-mentioned viruses.
The isolation of hypericin from Hypericum plants is not feasible on a larger scale, because it requires a lengthy procedure involving extraction with large volumes of solvents and cumbersome chromatographic separations on silica gel columns. The main difficulty in obtaining hypericin in a pure state from the plant material resides in its separation from the accompanying pseudohypericin. This necessitates the aforementioned chromatography with the elution of a large number of fractions, only a few of which contain the pure desired material. The yield of hypericin from the plants is very low, not more than 0.3%, based on the dry plant material.
A number of synthetic routes for hypericin have also been reported. One is a total synthesis starting from 3,5-dimethoxybenzoic acid methyl ester and requiring 12 process steps with an overall yield of ca. 6-9% (H. Brockman et al., Chem. Ber. 1957, 90, 2302).
The other syntheses use commercially available emodin as a starting material (for structure cf. Reaction Scheme). Emodin can be converted directly to protohypericin, a substituted helianthrone derivative which, on irradiation with visible light, is converted to hypericin. The first conversion involves treating a solution of emodin in aqueous base in the presence of hydroquinone in a sealed ampoule for 3 weeks at 120.degree. C. (H. J. Banks et al., Aust. J. Chem. 1976, 29, 1509; D. Spitzner, Angew. Chem. Int. Ed. Engl. 1977, 16, 46; G. Rodewald et al., ibid. 1977, 16, 46). The reported yield of protohypericin is not more than 29%. Besides this low yield, this synthesis has other drawbacks, namely the experimental difficulty in up-scaling this reaction, the large volumes of solvents needed for extraction, and the lengthy chromatographic separation.
Other syntheses also utilize emodin which is reduced to emodin anthrone (cf. Reaction Scheme). The latter can be oxidized to protohypericin in pyridine solution in the presence of piperidine. However, the yield of protohypericin and thus also of the derived hypericin was reported to be lower than ca. 10% (H. Brockman et al., Chem. Ber. 1958, 91, 547). This low yield necessitates special separation procedures which renders this method unsuitable for large scale production of hypericin. ##STR2## Alternatively, emodin anthrone can be oxidized to emodin bianthrone (cf. Reaction Scheme) which, in basic solution in the presence of air, yields protohypericin. The latter reaction could be successfully performed only on a very small scale (on ca. 10 mg). (D. W. Cameron et al,. Aust. J. Chem. 1976, 29, 1535; H. J. Banks et al., Aust. J. Chem. 1976, 29, 1509).
There exists, thus, an increasing need for a simple, efficient and economically feasible process for the synthesis of hypericin in comparatively high amounts, which process should avoid all the above-mentioned drawbacks of the prior art processes. It is the object of the present invention to fulfill this need.